Inflammation is induced in many conditions, including various tissue injuries and necrosis (a traumatic injury, a radiation injury, a cell injury due to an anti-cancer drug, an ischemic injury, a non-traumatic autoimmune disease, a tissue injury due to a rejection of transplant, and the like), foreign substance reaction, and infection. Inflammation may be locally induced or may be developed in response to sepsis, which induces inflammation all over the body, according to the degree of severity. Inflammation is a main cause of diseases for a large number of inflammatory diseases, for example, sepsis, arthritis, asthma, respiratory disease, respiratory syncitial virus (RSV) disease, radiation injury, stomach ulcer, gastroenteritis, diabetic ulcer, bedsore, nerve spinal injury, dementia, cornea injury, a skin wound, atopic dermatitis, cardiovascular disorders, autoimmune disease, rejection reaction of transplant, and the like, so that recently, many researchers are trying to inhibit inflammation processes. Continuous inflammation accelerates damage of tissue, so that nothing is more important than suitable inhibition of inflammation for treatment and survival of a patient.
An inflammatory cell is generated through several steps of differentiation processes from hematopoietic stem cells (HSC) in bone marrow like other hemocytes, and it is a one-way reaction so that once the cell is differentiated, the cell cannot be again returned to an undifferentiated state. Accordingly, as in the case of the other hemocytes, its life span is limited to between several days and several weeks, except for lymphocytes. Therefore, the generation of the cells of hematopoietic system occurs by continuous cell divisions and differentiations from hematopoietic stem cells throughout life. When an increase in inflammatory cells is required due to a tissue injury, the amount of HSC precursor cells having rapid division ability in bone marrow is increased so that the amount of hematopoietic stem cells is also increased in blood. The increased HSC begins to differentiate to a type of commitment hematopoietic progenitor cell. Therefore, a change of the amount of HSC in blood may significantly affect overall inflammation and immune response.
Inflammation is characterized by increased distributions of inflammatory hemocytoblasts (leukocytes, neutrophils, macrophages, and the like), precursor cells thereof, and HSCs in blood, an increase of inflammatory cytokines (TNF-alpha, IL2, IL4, IL6, and the like), and a decrease of anti-inflammatory cytokine (IL10, and the like) (Eva Mezey et al., Nature Medicine 2009, 15, 42-49). In addition, many inflammatory cells accumulate at a damaged tissue.
Generally, inflammation is one of the vital defense mechanisms in innate immune responses, but reactive oxygens, proteases, and the like that are secreted by inflammatory cells, especially, neutrophils, lead to severe injury of the surrounding tissues. Accordingly, an inflammation reaction is prolonged, thereby developing into a chronic or intractable ulcer, etc., which fibroses after curing, thereby causing sclerosis of tissue and so significantly decreasing tissue function.
A drug, such as an adrenocortical hormone and an anti-inflammatory analgesic drug, is now in use in order to treat inflammation, but an increased understanding at a molecular level about inflammation is expected to lead to development of a new drug for treating inflammation.
Recently, it is expected that IL-10, an anti-inflammatory cytokine, which is known to be secreted from anti-inflammatory macrophages (M2 type macrophage), regulatory T cells involved in inhibiting an autoimmune response, and the like, is involved in a decrease of inflammation and a decrease of autoimmune response, thereby minimizing tissue injury due to the inflammation and accelerating cure of tissue injury. There were attempts to control inflammation and autoimmune diseases by accelerating and controlling in vivo anti-inflammatory reaction based on the above-mentioned recent research results. However, a new material having a function for controlling inflammation has yet to be found.
Substance-P (hereinafter referred to as ‘Substance P’ or ‘SP’) has long been known to be a neurotransmitter transmitting pain in the central nervous system for. Substance-P is a peptide, which is composed of 11 amino acids, and a kind of neurohormone, in which there is no difference among species because it has the same amino acid sequence in human, mouse, and rabbit. Substance-P is expected to play an important role in a neuro-immune systems bidirectional regulation, myelofibrosis, cancer cell proliferation, and the like, in addition to pain transmission that is conventionally known, through expression and action in various tissues, such as non-nervous tissues, and the like, as well as nerve cells. In addition, the previous reports about Substance-P disclosed that Substance-P accelerates histamine release in a mast cell (Castellani M L et al., Clin Invest. Med. 2008, 31, E362-72), induces allodynia (McLeod A L et al., Neuroscience, 1999, 89, 891-9), and involves peripheral neuritis (Black P H, Brain Behay. Immun. 2002, 16, 622-53). It could be expected based on the above-mentioned reports that Substance-P may be a neurohormone inducing inflammation (proinflammatory neuropeptide) and may induce the same or more inflammation than that of G-CSF.
However, while comparing a function of Substance-P with a function of G-CSF, the present inventors found that Substance-P has rather an effect of inhibiting inflammation in various tissue injuries and thus completed the present invention.